Glutamate Dehydrogenase 1 Signals through Antioxidant Glutathione Peroxidase 1 to Regulate Redox Homeostasis and Tumor Growth

Lingtao Jin, Dan Li, Gina N. Alesi, Jun Fan, Hee Bum Kang, Zhou Lu, Titus J. Boggon, Peng Jin, Hong Yi, Elizabeth R. Wright, Duc Duong, Nicholas T. Seyfried, Robert Egnatchik, Ralph J. DeBerardinis, Kelly R. Magliocca, Chuan He, Martha L. Arellano, J. Hanna J Khoury, Dong M. Shin, Fadlo R. Khuri & 1 others Sumin Kang

Research output: Contribution to journalArticle

94 Citations (Scopus)

Abstract

How mitochondrial glutaminolysis contributes to redox homeostasis in cancer cells remains unclear. Here we report that the mitochondrial enzyme glutamate dehydrogenase 1 (GDH1) is commonly upregulated in human cancers. GDH1 is important for redox homeostasis in cancer cells by controlling the intracellular levels of its product alpha-ketoglutarate and subsequent metabolite fumarate. Mechanistically, fumarate binds to and activates a reactive oxygen species scavenging enzyme glutathione peroxidase 1. Targeting GDH1 by shRNA or a small molecule inhibitor R162 resulted in imbalanced redox homeostasis, leading to attenuated cancer cell proliferation and tumor growth.

Original languageEnglish (US)
Pages (from-to)257-270
Number of pages14
JournalCancer Cell
Volume27
Issue number2
DOIs
StatePublished - Feb 9 2015

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Glutamate Dehydrogenase
Oxidation-Reduction
Homeostasis
Antioxidants
Growth
Fumarates
Neoplasms
Enzymes
Small Interfering RNA
Reactive Oxygen Species
Cell Proliferation
glutathione peroxidase GPX1

ASJC Scopus subject areas

  • Cancer Research
  • Cell Biology
  • Oncology

Cite this

Glutamate Dehydrogenase 1 Signals through Antioxidant Glutathione Peroxidase 1 to Regulate Redox Homeostasis and Tumor Growth. / Jin, Lingtao; Li, Dan; Alesi, Gina N.; Fan, Jun; Kang, Hee Bum; Lu, Zhou; Boggon, Titus J.; Jin, Peng; Yi, Hong; Wright, Elizabeth R.; Duong, Duc; Seyfried, Nicholas T.; Egnatchik, Robert; DeBerardinis, Ralph J.; Magliocca, Kelly R.; He, Chuan; Arellano, Martha L.; Khoury, J. Hanna J; Shin, Dong M.; Khuri, Fadlo R.; Kang, Sumin.

In: Cancer Cell, Vol. 27, No. 2, 09.02.2015, p. 257-270.

Research output: Contribution to journalArticle

Jin, L, Li, D, Alesi, GN, Fan, J, Kang, HB, Lu, Z, Boggon, TJ, Jin, P, Yi, H, Wright, ER, Duong, D, Seyfried, NT, Egnatchik, R, DeBerardinis, RJ, Magliocca, KR, He, C, Arellano, ML, Khoury, JHJ, Shin, DM, Khuri, FR & Kang, S 2015, 'Glutamate Dehydrogenase 1 Signals through Antioxidant Glutathione Peroxidase 1 to Regulate Redox Homeostasis and Tumor Growth', Cancer Cell, vol. 27, no. 2, pp. 257-270. https://doi.org/10.1016/j.ccell.2014.12.006
Jin, Lingtao ; Li, Dan ; Alesi, Gina N. ; Fan, Jun ; Kang, Hee Bum ; Lu, Zhou ; Boggon, Titus J. ; Jin, Peng ; Yi, Hong ; Wright, Elizabeth R. ; Duong, Duc ; Seyfried, Nicholas T. ; Egnatchik, Robert ; DeBerardinis, Ralph J. ; Magliocca, Kelly R. ; He, Chuan ; Arellano, Martha L. ; Khoury, J. Hanna J ; Shin, Dong M. ; Khuri, Fadlo R. ; Kang, Sumin. / Glutamate Dehydrogenase 1 Signals through Antioxidant Glutathione Peroxidase 1 to Regulate Redox Homeostasis and Tumor Growth. In: Cancer Cell. 2015 ; Vol. 27, No. 2. pp. 257-270.
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